RESUMO
The latest advances in the sequencing methods in head and neck squamous cell carcinoma (HNSCC) tissues have revolutionized our understanding of the disease by taking off the veil from the most frequent genetic alterations in the components of the oncogenic pathways. Among all the identified alterations, aberrancies in the genes attributed to the phosphoinositide 3-kinases (PI3K) axis have attracted special attention as they were altered in more than 90% of the tissues isolated from HNSCC patients. In fact, the association between these aberrancies and the increased risk of cancer metastasis suggested this axis as an "Achilles Heel" of HNSCC, which may be therapeutically targeted. The results of the clinical trials investigating the therapeutic potential of the inhibitors targeting the components of the PI3K axis in the treatment of HNSCC patients, either alone or in a combined-modal strategy, opened a new chapter in the treatment strategy of this malignancy. The present study aimed to review the importance of the PI3K axis in the pathogenesis of HNSCC and also provide a piece of information about the breakthroughs and challenges of PI3K inhibitors in the therapeutic strategies of the disease.
Assuntos
Antineoplásicos/farmacologia , Neoplasias de Cabeça e Pescoço/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Neovascularização Patológica/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/genética , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Serina-Treonina Quinases TOR/metabolismoRESUMO
BACKGROUND: Transitional cell carcinoma (TCC) of the bladder is the second most common genitourinary malignancy. Because of the low sensitivity of urinary cytology and the invasiveness and expense of frequent cystoscopies for the detection of low-grade superficial lesions, we aim to establish a sensitive molecular approach to detect bladder cancer noninvasively. METHODS: Voided urine samples were collected from 80 patients with bladder cancer at the time of diagnosis, in addition to 30 patients with non-bladder cancer urological diseases and 20 healthy volunteers. The level of hTERT, KRT7, and survivin (SVV) mRNAs were analyzed using a qRT-PCR assay. RESULTS: The optimal threshold values for hTERT, KRT7, and SVV in urine were calculated by ROC curves analysis. The overall sensitivity was 81.3%, 91.3%, and 68.8% for hTERT, KRT7, and SVV, respectively, which were significantly higher than urine cytology (22.2%, p < 0.001). A higher positive ratio was obtained using multi-marker detection in comparison to single marker detection. The combined use of markers increased the sensitivity of cytology from 22.2 to 100%. In contrast with the urine cytology method, the sensitivity of these biomarkers was not correlated with the grades and stages of the bladder tumors. CONCLUSIONS: Our data indicate that urinary hTERT, KRT7, and SVV have superior sensitivities over cytology. The combined use of these markers offers a powerful potential assay and promising tool for a sensitive, noninvasive, and highly specific diagnostic method and follow-up of low-grade TCC of the bladder.
Assuntos
Carcinoma de Células de Transição/diagnóstico , Carcinoma de Células de Transição/urina , Queratina-7/urina , Reação em Cadeia da Polimerase em Tempo Real , Survivina/urina , Telomerase/urina , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/urina , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade NeoplásicaRESUMO
The success in the identification of BCR/ABL tyrosine kinase role in the pathogenesis of chronic myeloid leukemia (CML) went as far as to find a path to cure this leukemia; however, compensatory activation of leukomogenic signals get across the message that the small molecule inhibitors of oncogenic pathways, along with tyrosine kinase inhibitors, might be a beneficial approach in CML treatment. The results of the present study showed that the abrogation of the phosphoinositide 3-kinase (PI3K) pathway using pan-PI3K inhibitor BKM120 exerted a cytotoxic effect against CML-derived K562 cells through both the induction of p21-mediated G2/M arrest and the stimulation of apoptosis. Notably, the apoptotic effect of the inhibitor was further confirmed by the molecular analysis showing that BKM120 significantly increased the expression of pro-apoptotic genes. To the best of our knowledge, the involvement of autophagy in resistance to BKM120 has not been yet described and our study suggests for the first time that the elevation of autophagy-related genes might serve as a compensatory pathway to cease the anti-leukemic effect of BKM120 in K562; since we found a reinforced anti-survival event when the cells were treated with BKM120 in combination with autophagy inhibitor. In conclusion, the results of the present study showed that the abrogation of PI3K using BKM120 might be a befitting approach in CML treatment, either as a single agent or in a combined-modal strategy; however, further evaluations including clinical trials and in vivo investigations are demanded to ascertain the safety and the efficacy of the inhibitor in treatment strategies.
Assuntos
Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Morfolinas/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Autofagia , Sobrevivência Celular/efeitos dos fármacos , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológicoRESUMO
Despite an old history behind the identification of the leading role of c-Myc in leukemogenesis, the road to constructing a therapeutic perspective for this molecule in acute lymphoblastic leukemia (ALL) is yet mesmerizing. This study was designed to provide a better outlook for the anticancer property of 10058-F4, an appealing inhibitor of c-Myc, in pre-B ALL cell lines either in the context of monotherapy or in combination with chemotherapeutic drugs. Our results declared that abrogation of c-Myc decreased the proliferative capacity of pre-B ALL-derived cells through halting the transition of the cells from G1 phase, and reducing the replicative potential of both REH and Nalm-6 cells, at least partly, through c-Myc-mediated suppression of human telomerase reverse transcriptase. Moreover, 10058-F4 potently induced a caspase-3-dependent apoptosis in pre-B ALL cells via shifting the balance between pro- and anti-apoptotic target genes. Although the inhibition of PI3Kδ using Idelalisib upregulated the messenger RNA expression of autophagy-related genes in 10058-F4-treated cells, treatment with autophagy inhibitor chloroquine decreased viability of the cells, either as a single agent or in combination with Idelalisib and/or 10058-F4; suggesting that the activation of autophagy in pre-B ALL cells could blunt apoptotic events and attenuate anticancer effect of both c-Myc and PI3K inhibitors. Finally, the results of our synergistic experiments delineated that 10058-F4 produced a synergistic effect with vincristine and provided an enhanced therapeutic efficacy in ALL cells, highlighting that c-Myc oncoprotein could be a bona fide target for the treatment of ALL.
Assuntos
Apoptose , Caspase 3/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Tiazóis/uso terapêutico , Vincristina/uso terapêutico , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fase G1/efeitos dos fármacos , Humanos , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Purinas/farmacologia , Quinazolinonas/farmacologia , Telomerase/metabolismo , Tiazóis/farmacologiaRESUMO
Enthusiasms into the application of PI3K-δ inhibitor CAL-101 has been muted due to the over-activation of compensatory molecules. Our results delineated that c-Myc suppression using 10058-F4 enhanced CAL-101 cytotoxicity in less sensitive cells through different mechanisms based on p53 status; while CAL-101-plus-10058-F4 induced G1 arrest in wild-type p53-expressing leukemic cells, no conspicuous increase in G1 was noted in U937 cells harboring mutant p53. Conclusively, this study shed lights on the role of c-Myc oncoprotein in acute leukemia cells sensitivity to PI3K inhibitor and outlined that the combination of c-Myc inhibitor and CAL-101 may be a promising therapeutic approach in leukemia.
Assuntos
Antineoplásicos/farmacologia , Leucemia Mieloide Aguda/genética , Purinas/farmacologia , Quinazolinonas/farmacologia , Tiazóis/farmacologia , Proteína Supressora de Tumor p53/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismoRESUMO
Genetic and laboratory studies have remodeled the conventional understanding of cancer pathogenesis by identifying different molecular alterations. Intrigued by the contribution of neurokinin-1 receptor (NK1R) network in cancer pathogenesis, we investigated the antileukemic effects of aprepitant, a nonpeptide antagonist of NK1R, in a panel of hematological cell lines. In this study, we found that aprepitant decreased the survival of all the tested cells; however, as compared with NB4, viability of the other cell lines was inhibited at higher concentrations. By increasing both p21 and p73 along with suppressing c-Myc and hTERT, aprepitant probably disordered cell distribution in the cell cycle, decreased DNA replication rate, and, thereby, impeded the proliferative capability of NB4 cells. Moreover, exposing cells to this agent led to activation of the caspase-3-dependent apoptotic pathway through altering the expression of apoptosis-related genes. Noteworthy, aprepitant also sensitized NB4 cells to the cytotoxic effects of arsenic trioxide and vincristine. Overall, it seems that pharmaceutical targeting of NK1R using aprepitant, either as a single agent or in combination, possesses novel promising potential for leukemia treatment strategies.
Assuntos
Neoplasias Hematológicas/tratamento farmacológico , Morfolinas/farmacologia , Antagonistas dos Receptores de Neurocinina-1/farmacologia , Aprepitanto , Linhagem Celular Tumoral , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Humanos , Receptores da Neurocinina-1/metabolismoRESUMO
The frequency of dysregulated PI3K in acute lymphoblastic leukemia (ALL) coupled with the critical role of this signaling pathway in the acquisition of chemoresistant phenotype lend compelling weight to the application of PI3K inhibitors for the treatment of ALL. In this study, we found that abrogation of the PI3K pathway using CAL-101, a selective inhibitor of PI3K p110-δ, exerts a cytotoxic effect against Nalm-6 pre-B-ALL cells. Our results showed that the growth-suppressive effect is mediated, at least partially, by G1 arrest as a result of upregulated p21. CAL-101 also leads to induction of caspase-dependent apoptosis probably through reactive oxygen species-dependent upregulation of FOXO3a and subsequent induction of the proapoptotic target genes of p53. In conclusion, this study highlighted the potent efficacy of CAL-101 as either a single agent or in combination with doxorubicin in Nalm-6 cells; however, further investigation is needed to provide valuable clues to add this inhibitor for the treatment of ALL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Doxorrubicina/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Purinas/farmacologia , Quinazolinonas/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Doxorrubicina/administração & dosagem , Sinergismo Farmacológico , Inibidores Enzimáticos/farmacologia , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/enzimologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Purinas/administração & dosagem , Quinazolinonas/administração & dosagemRESUMO
As the fifth pillar of cancer treatment, immunotherapy has dramatically changed the paradigm of therapeutic strategies by focusing on the host's immune system. In the long road of immunotherapy development, the identification of immune-modulatory effects for kinase inhibitors opened a new chapter in this therapeutic approach. These small molecule inhibitors not only directly eradicate tumors by targeting essential proteins of cell survival and proliferation but can also drive immune responses against malignant cells. This review summarizes the current standings and challenges of kinase inhibitors in immunotherapy, either as a single agent or in a combined modality.
Assuntos
Neoplasias , Humanos , Neoplasias/tratamento farmacológico , ImunoterapiaRESUMO
Lipid signaling is defined as any biological signaling action in which a lipid messenger binds to a protein target, converting its effects to specific cellular responses. In this complex biological pathway, the family of phosphoinositide 3-kinase (PI3K) represents a pivotal role and affects many aspects of cellular biology from cell survival, proliferation, and migration to endocytosis, intracellular trafficking, metabolism, and autophagy. While yeasts have a single isoform of phosphoinositide 3-kinase (PI3K), mammals possess eight PI3K types divided into three classes. The class I PI3Ks have set the stage to widen research interest in the field of cancer biology. The aberrant activation of class I PI3Ks has been identified in 30-50% of human tumors, and activating mutations in PIK3CA is one of the most frequent oncogenes in human cancer. In addition to indirect participation in cell signaling, class II and III PI3Ks primarily regulate vesicle trafficking. Class III PI3Ks are also responsible for autophagosome formation and autophagy flux. The current review aims to discuss the original data obtained from international research laboratories on the latest discoveries regarding PI3Ks-mediated cell biological processes. Also, we unravel the mechanisms by which pools of the same phosphoinositides (PIs) derived from different PI3K types act differently.
Assuntos
Neoplasias , Fosfatidilinositol 3-Quinase , Animais , Humanos , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Autofagia , Mamíferos , LipídeosRESUMO
Purpose: Although the complex structure of acute lymphoblastic leukemia (ALL) and involvement of diverse pathways in its pathogenesis have put an obstacle in the way of efficient treatments, identification of strategies to manipulate the genome of neoplastic cells has made the treatment prospective more optimistic. Methods: To evaluate whether the transduction of apoptin __a gene encoding a protein that participates in the induction of apoptosis__ could reduce the survival of leukemic cells, we generated recombinant lentivirus expressing apoptin, and then, MTT assay, flow cytometric analysis of DNA content, western blotting, and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were applied. Results: Transduction of apoptin into different leukemic cells was coupled with the reduction in the viability and proliferative capacity of the cells. Among all tested cell lines, Nalm-6 and C8166 were more sensitive to the anti-leukemic property of apoptin. Moreover, we found that the transduction of apoptin in the indicated cell lines not only induced G2/M cell cycle arrest but also induced apoptotic cell death by altering the balance between pro- and anti-apoptotic target genes. The efficacy of apoptin transduction was not limited to these findings, as we reported for the first time that the overexpression of this gene could potentiate the anti-leukemic property of pan PI3K inhibitor BKM120. Conclusion: The results of this study showed that the transduction of apoptin into lymphoblastic leukemia cell lines induced cytotoxic effects and enhanced therapeutic value of PI3K inhibition; however, further investigations are demanded to ascertain the safety and the efficacy of apoptin transduction in patients with ALL.
RESUMO
Despite endorsed and exponential research to improve diagnostic and therapeutic strategies, efforts have not yet converted into a better prospect for patients infected with the novel coronavirus (2019nCoV), and still, the name of SARS-CoV-2 is coupled with numerous unanswered questions. One of these questions is concerning how this respiratory virus reduces the number of platelets (PLTs)? The results of laboratory examinations showed that about a quarter of COVID-19 cases experience thrombocytopenia, and more remarkably, about half of these patients succumb to the infection due to coagulopathy. These findings have positioned PLTs as a pillar in the management as well as stratifying COVID-19 patients; however, not all the physicians came into a consensus about the prognostic value of these cells. The current review aims to unravel the contributory role of PLTs s in COVID-19; and alsoto summarize the original data obtained from international research laboratories on the association between COVID-19 and PLT production, activation, and clearance. In addition, we provide a special focus on the prognostic value of PLTs and their related parameters in COVID-19. Questions on how SARS-CoV-2 induces thrombocytopenia are also responded to. The last section provides a general overview of the most recent PLT- or thrombocytopenia-related therapeutic approaches. In conclusion, since SARS-CoV-2 reduces the number of PLTs by eliciting different mechanisms, treatment of thrombocytopenia in COVID-19 patients is not as simple as it appears and serious cautions should be considered to deal with the problem through scrutiny awareness of the causal mechanisms.
Assuntos
Plaquetas/fisiologia , COVID-19/diagnóstico , COVID-19/fisiopatologia , Trombocitopenia/fisiopatologia , HumanosRESUMO
Among the long list of age-related complications, Alzheimer's disease (AD) has the most dreadful impact on the quality of life due to its devastating effects on memory and cognitive abilities. Although a plausible correlation between the phosphatidylinositol 3-kinase (PI3K) signaling and different processes involved in neurodegeneration has been evidenced, few articles reviewed the task. The current review aims to unravel the mechanisms by which the PI3K pathway plays pro-survival roles in normal conditions, and also to discuss the original data obtained from international research laboratories on this topic. Responses to questions on how alterations of the PI3K/Akt signaling pathway affect Tau phosphorylation and the amyloid cascade are given. In addition, we provide a general overview of the association between oxidative stress, neuroinflammation, alterations of insulin signaling, and altered autophagy with aberrant activation of this axis in the AD brain. The last section provides a special focus on the therapeutic possibility of the PI3K/Akt/mTOR modulators, either categorized as chemicals or herbals, in AD. In conclusion, determining the correct timing for the administration of the drugs seems to be one of the most important factors in the success of these agents. Also, the role of the PI3K/Akt signaling axis in the progression or repression of AD widely depends on the context of the cells; generally speaking, while PI3K/Akt activation in neurons and neural stem cells is favorable, its activation in microglia cells may be harmful.
Assuntos
Doença de Alzheimer/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Serina-Treonina Quinases TOR/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/genética , Autofagia/genética , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Terapia de Alvo Molecular , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/genética , Fosfatidilinositol 3-Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/uso terapêutico , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/uso terapêuticoRESUMO
The incidence of the novel coronavirus disease (COVID-19) outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has brought daunting complications for people as well as physicians around the world. An ever-increasing number of studies investigating the characteristics of the disease, day by day, is shedding light on a new feature of the virus with the hope that eventually these efforts lead to the proper treatment. SARS-CoV-2 activates antiviral immune responses, but in addition may overproduce pro-inflammatory cytokines, causing uncontrolled inflammatory responses in patients with severe COVID-19. This condition may lead to lymphopenia and lymphocyte dysfunction, which in turn, predispose patients to further infections, septic shock, and severe multiple organ dysfunction. Therefore, accurate knowledge in this issue is important to guide clinical management of the disease and the development of new therapeutic strategies in patients with COVID-19. In this review, we provide a piece of valuable information about the alteration of each subtype of lymphocytes and important prognostic factors associated with these cells. Moreover, through discussing the lymphopenia pathophysiology and debating some of the most recent lymphocyte- or lymphopenia-related treatment strategies in COVID-19 patients, we tried to brightening the foreseeable future for COVID-19 patients, especially those with severe disease.
Assuntos
Tratamento Farmacológico da COVID-19 , COVID-19/imunologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/virologia , Linfopenia/imunologia , Linfopenia/fisiopatologia , SARS-CoV-2/imunologia , COVID-19/complicações , Humanos , Linfopenia/etiologia , Linfopenia/virologia , PrognósticoRESUMO
The advent of tyrosine kinase inhibitors in the therapeutic protocols of chronic myeloid leukemia (CML) was a revolution in the treatment strategies that guaranteed the achievement of complete remission for patients. However, due to different mutations bypassing the efficacy of Imatinib, novel and more effective treatments are indeed required for the treatment of CML. Our study declared that the combination of synthesized ZnO/CNT@Fe3O4nanocomposite with Imatinib decreased survival of CML-derived K562 cells, probably through inducing reactive oxygen species-mediated apoptosis. We also found improved cytotoxicity in the presence of a well known autophagy inhibitor, indicating that the apoptotic effect of this treatment is enhanced via autophagy suppression. Investigating the molecular mechanisms for the growth-suppressive effect of ZnO/CNT@Fe3O4-plus-Imatinib suggested that up-regulation of SIRT1 ceased cell cycle progression by increasing the expression of p21 and p27 cyclin-dependent kinase inhibitors. Notably, we reported here for the first time that either direct or indirect suppression of c-Myc results in enhanced anti-leukemic efficacy, suggesting that overexpression of c-Myc plays a contributory role in attenuating the efficacy of ZnO/CNT@Fe3O4-Imatinib in K562 cells. Given the promising effect of ZnO/CNT@Fe3O4in potentiating the anti-cancer effects of Imatinib in K562 cells, our study suggested that nanocomposite could be used as a tool for combined-strategy treatment. However, furtherin vivoexperiments are needed to provide clues for the safety and efficacy of this nanocomposite.
Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Nanocompostos , Óxido de Zinco , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Resistencia a Medicamentos Antineoplásicos , Humanos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismoRESUMO
Genetic and epigenetic alterations have been under concentrated investigations for many years in order to unearth the molecules regulating human cancer pathogenesis. However, the identification of a wide range of dysregulated genes and their protein products has raised a question regarding how the results of this large collection of alterations could converge into a formation of one malignancy. The answer may be found in the signaling cascades that regulate the survival and metabolism of the cells. Aberrancies of each participant molecule of such cascades may well result in augmented viability and unlimited proliferation of cancer cells. Among various signaling pathways, the phosphatidylinositol-3-kinase (PI3K) axis has been shown to be activated in about one-third of human cancers. One of the malignancies that is mostly affected by this axis is gastric cancer (GC), one of the most fatal cancers worldwide. In the present review, we aimed to illustrate the significance of the PI3K/Akt/mTOR axis in the pathogenesis of GC and also provided a wide perspective about the application of the inhibitors of this axis in the therapeutic strategies of this malignancy.
Assuntos
Antineoplásicos/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Animais , Proliferação de Células , Humanos , Terapia de Alvo Molecular , Fosfatidilinositol 3-Quinase/genética , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Serina-Treonina Quinases TOR/genéticaRESUMO
BACKGROUND: The intertwining between cancer pathogenesis and aberrant expression of either oncogenes or tumor suppressor proteins ushered the cancer therapeutic approaches into a limitless road of modern therapies. For the nonce and among the plethora of promising anticancer agents, intense interest has focused on pioglitazone, a first in-class of Thiazolidinedione (TZD) drugs that is currently used to treat patients with diabetes. OBJECTIVE: Intrigued by the overexpression of PPARγ in Acute Promylocytic Leukemia (APL), this study was designed to investigate the effects of pioglitazone in APL-derived NB4 cells. METHODS: To assess the anti-leukemic effect of pioglitazone on myeloid leukemia cell lines, we used MTT and trypan blue assays. Given the higher expression level of PPARγ in NB4 cells, we then expanded our experiments on this cell line. To ascertain the molecular mechanism action of pioglitazone in APL-derived NB4 cells, we evaluated the expression levels of a large cohort of target genes responsible for the regulation of apoptosis, autophagy and cell proliferation. Afterward, to examine whether there is a correlation between PPARγ and the PI3K signaling pathway, the amount of Akt phosphorylation was evaluated using western blot analysis. RESULTS: Our results showed that pioglitazone exerted its cytotoxic effect in wild-type PTEN-expressing NB4 cells, but not in leukemic K562 cells harboring mutant PTEN; suggesting that probably this member of TZD drugs induced its anti-leukemic effects through a PTEN-mediated manner. Moreover, we found that not only pioglitazone reduced the survival rate of NB4 through the induction of p21-mediated G1 arrest, also elevated the intracellular level of Reactive Oxygen Species (ROS) which was coupled with upregulated FOXO3a. Notably, this study proposed for the first time that the stimulation of autophagy as a result of the compensatory activation of PI3K pathway may act as a plausible mechanism through which the anti-leukemic effect of pioglitazone may be attenuated; suggestive of the application of either PI3K or autophagy inhibitors along with pioglitazone in APL. CONCLUSION: By suggesting a mechanistic pathway, the results of the present study shed more light on the favorable anti-leukemic effect of pioglitazone and suggest it as a promising drug that should be clinically investigated in APL patients.
Assuntos
Antineoplásicos/farmacologia , Leucemia Promielocítica Aguda/tratamento farmacológico , PPAR gama/metabolismo , Pioglitazona/farmacologia , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Descoberta de Drogas , Humanos , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Pioglitazona/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Regulação para Cima/efeitos dos fármacosRESUMO
In the last three decades, the pathogenesis of acute promyelocytic leukemia (APL) has been mostly studied with regard to the oncogenic role of PML/RAR fusion protein; however, the latest discoveries have stated that the concerns with the treatment of APL patients would not be resolved until the role of aberrant networks is overlooked. The present study was designed to evaluate the anti-cancer property of second-generation of the proteasome inhibitors carfilzomib (CFZ) on APL-derived NB4 cells. Our results showed that pharmacologic targeting of proteasome in NB4 reduced the proliferative rate of malignant cells through a c-Myc-mediated G2/M cell cycle arrest. Moreover, we found that the suppression of proteasome was coupled with the induction of apoptotic NB4 cell death, which is probably mediated through down-regulation of anti-apoptotic target genes. Interestingly, our results suggested that the suppression of the autophagy system using chloroquine could serve as a mechanism through which the cytotoxicity of CFZ in APL cells was ameliorated. Finally, and consistent with the favorable efficacy of single agent of CFZ, we also noted an intensifying effect of the inhibitor on the anti-leukemic activity of arsenic trioxide (ATO) when it was used in combination. Overall, this study suggests that pharmaceutical targeting of proteasome using CFZ, either as a single agent or in combination with ATO, could be a promising mechanism through which the obstacle on the way of APL would be tackled; however, further investigations are needed to determine the advantages of the inhibitor in clinical applications.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Trióxido de Arsênio/farmacologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Inibidores de Proteassoma/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Trióxido de Arsênio/uso terapêutico , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Leucemia Promielocítica Aguda/patologia , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/uso terapêuticoRESUMO
The emergence of the drugs targeting epigenetic alterations has brought an optimistic outlook for cancer patients and probably put an end into the devastating effects of the disease. Given to the prominent involvement of histone deacetylase (HDAC) enzymes in the formation of neoplastic nature of acute promyelocytic leukemia (APL), this study was aimed to evaluate the suppressive effect of pan-HDAC inhibitor panobinostat on both NB4 and primary APL patients cells, either in the context of mono- or co-culture with mesenchymal stem cells (MSC). Panobinostat effectively reduced the survival of APL cells; however, as compared to NB4, the viability of primary cells was inhibited at higher concentrations. Our results also showed that although HDAC inhibition could merely block the survival signals transduced from MSC, the presence of PI3K inhibitor could robustly reinforce panobinostat cytotoxicity; suggesting that MSC-induced activation of PI3K may attenuate, at least partly, the efficacy of HDAC inhibition in APL cells. In addition, cellular and molecular investigations on NB4 revealed that not only panobinostat induced p21-mediated G1 arrest and ROS-mediated apoptosis, but also exerted a superior cytotoxicity when combined with c-Myc and autophagy inhibitors. Last but not least, we found that panobinostat combined with arsenic trioxide (ATO) prompted a synergistic effect and provided an improved therapeutic value in NB4; proposing that the abrogation of HDAC using panobinostat might be a befitting approach in APL, either as a single agent or in a combined-modal strategy.
Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Promielocítica Aguda/tratamento farmacológico , Panobinostat/uso terapêutico , Fosfatidilinositol 3-Quinases/uso terapêutico , Antineoplásicos/farmacologia , Apoptose , Humanos , Leucemia Promielocítica Aguda/patologia , Panobinostat/farmacologia , Fosfatidilinositol 3-Quinases/farmacologiaRESUMO
The advent of nanoparticles revolutionised the drug delivery systems in human diseases; however, their prominent role was highlighted in the cancer-based therapies, where this technology could specifically target cancer cells. Herein, we decided to combine two nanoparticles Fe3O4 and ZnO to fabricate a new anti-cancer nanocomposite. Noteworthy, hydroxylated carbon nanotube (CNT) was used to increase the water-solubility of the compound, improving its uptake by malignant cells. This study was designed to evaluate the anticancer property as well as the molecular mechanisms of ZnO/CNT@Fe3O4 nanocomposite cytotoxicity in CML-derived K562 cells. Our results outlined that ZnO/CNT@Fe3O4 decreased the proliferative capacity of K562 cells through induction of G1 arrest and induced apoptosis probably via ROS-dependent upregulation of FOXO3a and SIRT1. The results of qRT-PCR analysis also demonstrated that while ZnO/CNT@Fe3O4 significantly increased the expression of pro-apoptotic genes in K562 cells, it had no significant inhibitory effect on the expression levels of anti-apoptotic target genes of NF-κB; proposing an attenuating role of NF-κB signalling pathway in K562 cell response to ZnO/CNT@Fe3O4. Synergistic experiment showed that ZnO/CNT@Fe3O4 could enhance the cytotoxic effects of imatinib on K562 cells. Overall, it seems that pharmaceutical application of nanocomposites possesses novel promising potential for leukaemia treatment strategies.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Óxido Ferroso-Férrico/química , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Nanotubos de Carbono/química , Óxido de Zinco/química , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/genética , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Óxido Ferroso-Férrico/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Mesilato de Imatinib/farmacologia , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Nanocompostos/química , Nanocompostos/uso terapêutico , Nanopartículas/química , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/genética , Óxido de Zinco/farmacologiaRESUMO
Unlike the broad spectrum efficacies in wiping the malignant cells out, application of vincristine (VCR) in acute lymphoblastic leukemia (ALL) therapeutic protocol is partially restricted due to its high frequent resistant rate. Although several mechanisms have been enumerated for VCR resistance, to the best of our knowledge, there is no report reflecting the suppressive effect of oncogenic pathways on VCR cytotoxicity in ALL. The results of the present study indicated that both pre-B ALL-derived REH and Nalm-6 cells were partly resistant to VCR, with this note that Nalm-6 cells displayed more resistant phenotype. More interestingly, we showed for the first time that among inhibitors of different signaling pathways including those targeting PI3K, ERK, and NF-κB, the enhancive effect of small molecule inhibitor of c-Myc 10058-F4 was more significant on VCR cytotoxicity. Inhibition of c-Myc in VCR-treated Nalm-6 cells promoted a caspase-3-dependent apoptosis not only through altering the balance between death promoters to death suppressors, but also via modulating the expression of autophagy-related genes. Noteworthy, favorable impact of 10058-F4 on VCR anti-leukemic effect was not restricted to the induction of cell death and this agent also reinforced VCR anti-proliferative effect through disturbing cell cycle progression and hampering the expression of Pin1 and hTERT. In conclusion, it seems that targeting c-Myc could produce a synergistic anti-cancer effect with VCR and provide a fundamental infrastructure for a promising approach in ALL.